The decline in skeletal muscle function as we age impairs quality of life and increases frailty. The impairment of muscle stem cells, called satellit cells (SCs), which repair and rebuild muscle, contributes to the decline in muscle regeneration. SCs are rare and typically quiescent. They are dispersed throughout skeletal muscle tissue, and upon activation can either differentiate to form new muscle fibers or self-renew to create new SCs. An attractive long-term treatment for muscle deterioration is to transplant SCs directly into old or diseased muscle in hopes of boosting SC numbers and function to improve muscle regeneration. However, significant hurdles for cell-based therapies exist including immune rejection, insufficient numbers of donor cells and methods for systemic delivery of donor cells. A strategy to avoid these difficulties would be to expand and promote endogenous SC function. To implement this strategy we must first understand the signaling pathways that regulate endogenous SC expansion and function in vivo. Signaling through the receptor tyrosine kinase, fibroblast growth factor receptor 1 (FGFR1) regulates SCs by blocking differentiation and promoting self- renewal. Impaired FGFR1 signaling in SCs from old mice promotes differentiation at the expense of self- renewal but transient in vitro correction of FGFR1 signalin restores SC self-renewal. Preliminary data suggests that induction of a constitutively active FGFR1 (referred to as FGFR1*) increases the number of SCs in young muscle. How this system alters SC fate decisions to cause expanded numbers or what effect boosting endogenous SC numbers has on regeneration is unknown. Using FGFR1* mice, I plan to determine if expanding SC numbers in young muscle by FGFR1 activation can enhance muscle regeneration (Aim 1). I will also determine if the rescue of the SC-autonomous defect in FGFR1 signaling has the potential to improve SC function in old muscle (Aim 2). Results generated from young muscle experiments will inform experiments on FGFR1 activation in SCs of aged muscle. The proposed experiments will provide insight into the ability of FGFR1 signaling to increase SC numbers, enhance regeneration and rescue age-related muscle degeneration. The experiments in this proposal represent a critical step toward uncovering the potential role of FGFR1 as a therapeutic target for muscle regeneration.